Tunable and fast-cured hyaluronic acid hydrogel inspired on catechol architecture for enhanced adhesion property.

Hyaluronic acid-based hydrogels have been broadly used in medical applications due to their remarkable properties such as biocompatibility, biodegradability, super hydroscopicity, non-immunogenic effect, etc. However, the inherent weak and hydrophilic polysaccharide structure of pure hyaluronic acid (HA) hydrogels has limited their potential use in muco-adhesiveness, wound dressing, and 3D printing. In this research, we developed in-situ forming of catechol-modified HA hydrogels with improved mechanical properties involving blue-light curing crosslinking reaction. The effect of catechol structure on the physicochemical properties of HA hydrogels was evaluated by varying the content (0-40 %). The as-synthesized hydrogel demonstrated rapid prototyping, excellent wetting adhesiveness, and good biocompatibility. Furthermore, an optimized hydrogel precursor solution was used as a blue light-cured bio-ink with high efficiency and good precision and successfully prototyped a microstructure that mimicked the human hepatic lobule by using DLP 3D printing method. This catechol-modified HA hydrogel with tunable physicochemical and rapid prototyping properties has excellent potential in biomedical engineering.

A Nature-Derived, Hetero-Structured, Pro-Healing Bioadhesive Patch for High-Performance Sealing of Wet Tissues.

Tissue adhesives are promising alternatives to sutures and staples to achieve wound closure and hemostasis. However, they often do not work well on tissues that are soaked in blood or other biological fluids, and organs that are typically exposed to a variety of harsh environments such as different pH values, nonhomogeneous distortions, continuous expansions and contractions, or high pressures. In this study, a nature-derived multilayered hetero-bioadhesive patch (skin secretion of Andrias davidianus (SSAD)-Patch) based on hydrophilic/hydrophobic pro-healing bioadhesives derived from the SSAD is developed, which is designed to form pressure-triggered strong adhesion with wet tissues. The SSAD-Patch is successfully applied for the sealing and healing of tissue defects within 10 s in diverse extreme injury scenarios in vivo including rat stomach perforation, small intestine perforation, fetal membrane defect, porcine carotid artery incision, and lung lobe laceration. The findings reveal a promising new type of self-adhesive regenerative SSAD-Patch, which is potentially adaptable to broad applications (under different pH values and air or liquid pressures) in sutureless wound sealing and healing.

Generation and characterization of nanobodies targeting human pepsinogens.

Human pepsinogens (mainly pepsinogen I and pepsinogen II) are the major inactive precursor forms of the digestive enzyme pepsin which play a crucial role in protein digestion. The levels and ratios of human pepsinogens have demonstrated potential as diagnostic biomarkers for gastrointestinal diseases, particularly gastric cancer. Nanobodies are promising tools for the treatment and diagnosis of diseases, owing to their unique recognition properties. In this study, recombinant human pepsinogens proteins were expressed and purified as immunized antigens. We constructed a VHH phage library and identified several nanobodies via phage display bio-panning. We determined the binding potency and cross-reactivity of these nanobodies. Our study provides technical support for developing immunodiagnostic reagents targeting human pepsinogens.

A compendium of genetic regulatory effects across pig tissues.

The Farm Animal Genotype-Tissue Expression (FarmGTEx) project has been established to develop a public resource of genetic regulatory variants in livestock, which is essential for linking genetic polymorphisms to variation in phenotypes, helping fundamental biological discovery and exploitation in animal breeding and human biomedicine. Here we show results from the pilot phase of PigGTEx by processing 5,457 RNA-sequencing and 1,602 whole-genome sequencing samples passing quality control from pigs. We build a pig genotype imputation panel and associate millions of genetic variants with five types of transcriptomic phenotypes in 34 tissues. We evaluate tissue specificity of regulatory effects and elucidate molecular mechanisms of their action using multi-omics data. Leveraging this resource, we decipher regulatory mechanisms underlying 207 pig complex phenotypes and demonstrate the similarity of pigs to humans in gene expression and the genetic regulation behind complex phenotypes, supporting the importance of pigs as a human biomedical model.

Dental Pulp Stem Cells for Bone Tissue Engineering: A Literature Review.

Bone tissue engineering (BTE) is a promising approach for repairing and regenerating damaged bone tissue, using stem cells and scaffold structures. Among various stem cell sources, dental pulp stem cells (DPSCs) have emerged as a potential candidate due to their multipotential capabilities, ability to undergo osteogenic differentiation, low immunogenicity, and ease of isolation. This article reviews the biological characteristics of DPSCs, their potential for BTE, and the underlying transcription factors and signaling pathways involved in osteogenic differentiation; it also highlights the application of DPSCs in inducing scaffold tissues for bone regeneration and summarizes animal and clinical studies conducted in this field. This review demonstrates the potential of DPSC-based BTE for effective bone repair and regeneration, with implications for clinical translation.

GLP-1 receptor agonists for the treatment of obesity: Role as a promising approach.

Obesity is a complex disease characterized by excessive fat accumulation which is caused by genetic, environmental and other factors. In recent years, there has been an increase in the morbidity, disability rate,and mortality due to obesity, making it great threat to people's health and lives, and increasing public health care expenses. Evidence from previous studies show that weight loss can significantly reduce the risk of obesity-related complications and chronic diseases. Diet control, moderate exercise, behavior modification programs, bariatric surgery and prescription drug treatment are the major interventions used to help people lose weight. Among them, anti-obesity drugs have high compliance rates and cause noticeable short-term effects in reducing obese levels. However, given the safety or effectiveness concerns of anti-obesity drugs, many of the currently used drugs have limited clinical use. Glucagon-like peptide-1 receptor (GLP-1R) agonists are a group of drugs that targets incretin hormone action, and its receptors are widely distributed in nerves, islets, heart, lung, skin, and other organs. Several animal experiments and clinical trials have demonstrated that GLP-1R agonists are more effective in treating or preventing obesity. Therefore, GLP-1R agonists are promising agents for the treatment of obese individuals. This review describes evidence from previous research on the effects of GLP-1R agonists on obesity. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop obesity treatments based on GLP-1R agonists.

Hydroxyurea ameliorates atherosclerosis in ApoE-/- mice by potentially modulating Niemann-Pick C1-like 1 protein through the gut microbiota.

Rationale: The efficacy and mechanism of hydroxyurea in the treatment of atherosclerosis have rarely been reported. The goal of this study was to investigate the efficacy of hydroxyurea in high-fat diet-fed ApoE-/- mice against atherosclerosis and examine the possible mechanism underlying treatment outcomes. Methods: ApoE-/- mice were fed a high-fat diet for 1 month and then administered hydroxyurea by gavage continuously for 2 months. Aortic root hematoxylin-eosin (H&E) staining and oil red O staining were used to verify the efficacy of hydroxyurea; biochemical methods and ELISA were used to detect changes in relevant metabolites in serum. 16S rRNA was used to detect composition changes in the intestinal bacterial community of animals after treatment with hydroxyurea. Metabolomics methods were used to identify fecal metabolites and their changes. Immunohistochemical staining and ELISA were used for the localization and quantification of intestinal NPC1L1. Results: We showed that aortic root HE staining and oil red O staining determined the therapeutic efficacy of hydroxyurea in the treatment of atherosclerosis in high-fat diet-fed ApoE-/- mice. Serological tests verified the ability of hydroxyurea to lower total serum cholesterol and LDL cholesterol. The gut microbiota was significantly altered after HU treatment and was significantly different from that after antiplatelet and statin therapy. Meanwhile, a metabolomic study revealed that metabolites, including stearic acid, palmitic acid and cholesterol, were significantly enriched in mouse feces. Further histological and ELISAs verified that the protein responsible for intestinal absorption of cholesterol in mice, NPC1L1, was significantly reduced after hydroxyurea treatment. Conclusions: In high-fat diet-fed ApoE-/- mice, hydroxyurea effectively treated atherosclerosis, lowered serum cholesterol, modulated the gut microbiota at multiple levels and affected cholesterol absorption by reducing NPC1L1 in small intestinal epithelial cells.

Giant left coronary artery diagonal branch left ventricular fistula: A case report and review of literature.

A 37-year-old Chinese man was admitted to the department of cardiology of the First Hospital of Jilin University for intermittent palpitation for 9 months, aggravating with chest pain for 3 days. After several examinations, he was diagnosed with giant left ventricular fistula of the diagonal branch of the left coronary artery. After routine treatment, which included improving circulation and administration of dual antiplatelet as well as hypolipidemic drugs among others, the patient's symptoms did not improve. The fistula was too big for transcatheter occlusion to be performed. A multi-disciplinary suggestion was that the patient be subjected to "surgical closure treatment"; however, for personal reasons, he refused the operation. After discharge, oral beta-blockers were prescribed for the patient. Incidences of congenital coronary arterial fistula in congenital cardiovascular disease are rare, and incidences of the giant fistula being located in the left heart system are even rarer. We report an adult male with a giant left anterior descending diagonal coronary artery left ventricular fistula and show various accessory examination results. Non-invasive ultrasonic cardiography was the first diagnostic option for the disease and pre-admission evaluation. Auxiliary diagnosis and exclusion value of cardiovascular magnetic resonance (CMR) were revealed for the first time. Invasive coronary angiography (ICA) was demonstrated to be the gold standard method again and it was also found that computed tomography angiography (CTA) might be used instead of ICA for determining the exact relationships among anatomic structures. Furthermore, we performed a literature review on the diagnosis and treatment of patients with this condition.

The current strategies of optimization of oseltamivir against mutant neuraminidases of influenza A：A review.

Influenza with a tendency to cause pandemic and epidemic is an infectious disease with a high of morbidity and mortality. Neuraminidase (NA) inhibitors are proved to prevent and treat influenza. Among the four Neuraminidase inhibitors (NAIs) licensed, oseltamivir is most commonly used. With the extensive usage, several variants containing mutant NAs especially H274Y point mutation exhibit reduced susceptibility. In this review, we covered the current drugs available for influenza, the analysis of active site of NA, the mutant types of NAs and the molecular mechanism of drug resistance brought by H274Y mutant NAs. For recovering the susceptibility to oseltamivir, many series of oseltamivir analogues were designed. We present the details of the strategies of strengthening the interactions with S2 via introducing strong basic fragment, targeting additional subpockets and making full use of Zone X by modifying 3-pentyl of OC. PROTAC targeting NA and combination therapies are also introduced. Further, the advantages and disadvantages of these methods are also discussed.

Comparison of Immune Responses Elicited by SARS-CoV-2 mRNA and Recombinant Protein Vaccine Candidates.

After the outbreak of COVID-19, billions of vaccines with different types have been administrated, including recombinant protein vaccines and mRNA vaccines. Although both types of SARS-CoV-2 vaccine can protect people from viral infection, their differences in humoral and cellular immune responses are still not clearly understood. In this study, we made a head-to-head comparison between an mRNA vaccine candidate and a recombinant protein vaccine we developed previously. Results demonstrated that both vaccine candidates could elicit high specific binding and neutralizing antibody titers in BALB/c mice, but with bias towards different IgG subtypes. Besides, the mRNA vaccine candidate induces higher cellular immune responses than the recombinant protein vaccine. To date, this is the first reported study to directly compare the immune responses of both arms between SARS-CoV-2 mRNA and recombinant vaccines.

Optical elliptic breathers in isotropic nonlocal nonlinear media.

We investigate the propagation dynamics of elliptic Gaussian breathers without and with orbital angular momentum (OAM) in thermal nonlocal nonlinear media with both linear and nonlinear isotropy. The beamwidths and intensity of the elliptic breather without OAM, and the beamwidths and rotation angle of the elliptic breather with the critical OAM are analytically discussed in details. In experiment, the OAM-free elliptic beam is observed to oscillate and cannot form an elliptic soliton for any input power. By contrast, the elliptic beam carrying the critical OAM can keep its ellipticity changeless during the propagation and evolve into a spiralling elliptic soliton at the critical power. Specifically, in the vicinity of the critical power, the rotation angle of the spiralling elliptic beam can be controlled linearly by the input power and exceed π/2, while its beamwidths and ellipticity remain unchanged. Such a power-controllable, profile-preserving spiralling elliptic beam may provide potential applications in all-optical manipulation.

Genome-wide identification and evolution of WNK kinases in Bambusoideae and transcriptional profiling during abiotic stress in Phyllostachys edulis.

With-no-lysine (WNK) kinases play vital roles in abiotic stress response, circadian rhythms, and regulation of flowering time in rice, Arabidopsis, and Glycine max. However, there are no previous reports of WNKs in the Bambusoideae, although genome sequences are available for diploid, tetraploid, and hexaploid bamboo species. In the present study, we identified 41 WNK genes in five bamboo species and analysed gene evolution, phylogenetic relationship, physical and chemical properties, cis-elements, and conserved motifs. We predicted the structure of PeWNK proteins of moso bamboo and determined the exposed, buried, structural and functional amino acids. Real-time qPCR analysis revealed that PeWNK5, PeWNK7, PeWNK8, and PeWNK11 genes are involved in circadian rhythms. Analysis of gene expression of different organs at different developmental stages revealed that PeWNK genes are tissue-specific. Analysis of various abiotic stress transcriptome data (drought, salt, SA, and ABA) revealed significant gene expression levels in all PeWNKs except PeWNK11. In particular, PeWNK8 and PeWNK9 were significantly down- and up-regulated, respectively, after abiotic stress treatment. A co-expression network of PeWNK genes also showed that PeWNK2, PeWNK4, PeWNK7, and PeWNK8 were co-expressed with transcriptional regulators related to abiotic stress. In conclusion, our study identified the PeWNKs of moso bamboo involved in circadian rhythms and abiotic stress response. In addition, this study serves as a guide for future functional genomic studies of the WNK genes of the Bambusoideae.

Molecular-level insights into the immobilization of vapor-phase mercury on Fe/Co/Ni-doped hierarchical molybdenum selenide.

A novel and efficient adsorbent (TM-MoSe2, TM = Fe, Co, Ni) for mercury removal was developed and studied. The adsorption of mercury species (Hg0, HgCl, and HgCl2) and the oxidation of Hg0 by HCl on TM-MoSe2 (001) surface were explored at molecular level by density functional theory (DFT). The results shown that the Hg0 adsorption capacity of MoSe2 was improved by the doping of Fe/Co/Ni, which was also confirmed by experiments. The initial Hg0 removal efficiency of MoSe2-based adsorbents reached 96.4-100.0%. In addition, HgCl was mainly adsorbed on TM-MoSe2 (001) surface in the form of dissociation. The escape of Hg atom from HgCl resulted in the release of Hg0 again. However, HgCl2 could be fixed well on the surface of adsorbent through molecular adsorption or dissociative adsorption. For the oxidation process of Hg0 by HCl, it abided with the Langmuir-Hinshelwood mechanism. In comparison with direct oxidation (Hg → HgCl2), two-step pathway (Hg → HgCl → HgCl2) was an achievable reaction route with lower energy. Furthermore, the Hg → HgCl process was the rate-limiting step of the two-step pathway. The proposed adsorption and oxidation mechanism of mercury species on TM-MoSe2 (001) provide advanced strategies on the development of adsorbents for industrial mercury removal.

Discovery of hydrazide-containing oseltamivir analogues as potent inhibitors of influenza A neuraminidase.

Neuraminidase (NA) inhibitors play a prime role in treating influenza. However, a variety of viruses containing mutant NAs have developed severe drug resistance towards NA inhibitors, so it is of crucial significance to solve this problem. Encouraged by urea-containing compound 12 disclosed by our lab, we designed a series of oseltamivir derivatives bearing hydrazide fragment for targeting the 150 cavity. Among the synthesized compounds, compound 17a showed 8.77-fold, 4.12-fold, 203-fold and 6.23-fold more potent activity than oseltamivir carboxylate against NAs from H5N1, H1N1, H5N1-H274Y, H1N1-H274Y, respectively. Meanwhile, the best compound 17a exhibited satisfactory metabolic stability in vitro. This study offers an important reference for the structural optimization of oseltamivir aiming at potent inhibition against H274Y mutant of NAs.

Rapid and quantitative detection of Shiga toxin1 and Shiga toxin2 based on multiple targets UPT-LF assay.

Shiga toxin-producing Escherichia coli (STEC) infection causes a series of diseases that are highly pathogenic and deadly in humans and animals, seriously endangering public health. Of the pathogenic factors within STEC, the two groups of Shiga toxin (Stx) consisting Stx1 and Stx2 plays a prominent role in the pathogenesis of STEC infection. In this study, we developed single-target up-converting phosphor technology-based lateral flow assay (Stx-UPT-LFA) for the rapid detection of Stx1 and Stx2, respectively, and also developed a dual-target Stx1/2-UPT-LFA based on single-target strips to detect of Stx1 and Stx2 at the meantime within 20 min. We choose the purified Stx1 and Stx2 standard samples, and the optimum monoclonal antibody (namely 8E7-E6, 2F6-F8 for Stx1 and S1D8, S2C4 for Stx2) were selected for use in Stx-UPT-LFA in double-antibody-sandwich mode. The sensitivities of single-target Stx-UPT-LFA for both Stx1 and Stx2 were 1 ng mL-1 with accurate quantitation ranges of 1-1000 ng mL-1 and 1-800 ng mL-1 respectively. No false-negative result was found in the Stx2-UPT-LFA even with a high-test concentration up to 1000 ng mL-1. Meanwhile, both targets detection sensitivities for dual-target Stx1/2-UPT-LFA were 5 ng mL-1, and accurate quantitation ranges were 5-1000 ng mL-1 and 5-800 ng mL-1 for standard Stx1 and Stx2 solutions without cross-interference between two targets. Both techniques showed good linearities, with a linear fitting coefficient of determination(r) of 0.9058-0.9918. Therefore, the UPT-LFA could realize simultaneous detection for multiple targets on a single strip and thus to quickly determine the type of infectious Stxs. In addition, the single-target Stx1-UPT-LFA and Stx2-UPT-LFA showed excellent specificity to six toxins, even at high concentrations of 1000 ng mL-1. In conclusion, the developed Stx-UPT-LFA allows the rapid, quantitative, reliable and simultaneous detection of Stx1 and Stx2 within 20 min, providing an alternative method for clinical diagnosis of STEC infection.

In situ apolipoprotein E-enriched corona guides dihydroartemisinin-decorating nanoparticles towards LDLr-mediated tumor-homing chemotherapy.

The therapeutic efficiency of active targeting nanoparticulate drug delivery systems (nano-DDS) is highly compromised by the plasma proteins adsorption on nanoparticles (NPs) surface, which significantly hinders cell membrane receptors to recognize the designed ligands, and provokes the off-target toxicity and rapid clearance of NPs in vivo. Herein, we report a novel dihydroartemisinin (DHA)-decorating nano-DDS that in situ specifically recruits endogenous apolipoprotein E (apoE) on the NPs surface. The apoE-anchored corona is able to prolong PLGA-PEG2000-DHA (PPD) NPs circulation capability in blood, facilitate NPs accumulating in tumor cells by the passive enhanced permeability and retention (EPR) effect and low-density lipoprotein receptor (LDLr)-mediated target transport, and ultimately improve the in vivo antitumor activity. Our findings demonstrate that the strategy of in situ regulated apoE-enriched corona ensures NPs an efficient LDLr-mediated tumor-homing chemotherapy.

Discovery of a non-zwitterionic oseltamivir analogue as a potent influenza a neuraminidase inhibitor.

The most of potent neuraminidase inhibitors as zwitterions with poor lipophilicity suffered from the poor oral bioavailability. Herein, we describe a rational journey to discover a non-zwitterionic neuraminidase inhibitor 24a containing urea. It showed potent inhibitions against neuraminidases from group 1(H5N1 and H1N1) and group 2 (H3N2) subtypes and exhibited more strong inhibitory activities against neuraminidases from H274Y mutants than oseltamivir carboxylate. Whether administrated by orally or intravenous injection, the pharmacokinetic profile of compound 24a in SD rats were improved compared to oseltamivir carboxylate.

Polydopamine-doped virus-like mesoporous silica coated reduced graphene oxide nanosheets for chemo-photothermal synergetic therapy.

Multifunctional nanocarriers have been widely accepted and utilized for biomedical applications, because of their structural regularity, convenient post-modification and controllable structure and morphology. Herein, we reported polydopamine-doped virus-like mesoporous silica coated reduced graphene oxide nanosheets (rGO@PVMSNs) nanocomposites by a facile oil-water biphase stratification method. The synthesized rGO@PVMSNs nanocomposites performed excellent biocompatibility and photothermal performance. They could be employed as photoacoustic imaging contrast in vivo. Furthermore, the rGO@PVMSNs nanocarriers were used for loading the antitumor drug doxorubicin (DOX), the rGO@PVMSNs@DOX nanocomposites were also demonstrated to be with high inhibition of HepG2 cancer cells, especially with the help of near-infrared irradiation, which were more efficient than single chemotherapy or photothermal therapy. The rGO@PVMSNs@DOX nanocomposites of this work could be used as photoacoustic imaging and chemo-photothermal synergetic therapy agents, which show a new perspective for clinical tumor diagnosis and therapy.

Higher-charge vortex solitons and vector vortex solitons in strongly nonlocal media.

We report, to the best of our knowledge, the first experimental observation of higher-charge vortex solitons and vector vortex solitons in lead glass with strongly thermal nonlocal nonlinearity. A higher-charge vortex soliton with a topological charge of l=4 and a vector vortex soliton consisting of two orthogonally polarized vortex components, with charges l1=1 and l2=4, were observed at several times of diffraction length. We show that the ring profiles and the carried topological charges of the two incoherently coupled vortex components can be preserved. We also numerically find that the stability of the higher-charge vortex can be enhanced by co-propagating a stable, single-charge vortex.

Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy.

Hyaluronic acid (HA) is a natural ligand of tumor-targeted drug delivery systems (DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors (HARE and LYVE-1) are also overexpressing in the reticuloendothelial system (RES). Therefore, polyethylene glycol (PEG) modification of HA-based DDS is necessary to reduce RES capture. Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement, significantly compromising the in vivo antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform (Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage. The in vitro and in vivo investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and in vivo nonspecific biodistribution.